Abstract The majority of people diagnosed with acute myelogenous leukemia (AML) die of their disease, despite availability of active standard chemotherapy regimens, targeted therapies, and allogeneic transplantation. We have found that we can probe mitochondrial apoptotic signaling of patient myeloblasts to identify active therapies in AML using BH3 profiling. Prior exploitation of BH3 profiling led to the FDA approval of venetoclax in combination with hypomethylating agents or low-dose cytarabine. Here we present an innovation, Dynamic BH3 Profiling, which we propose to use to identify active single agents as well as combinations in AML. High priority will be given to combinations with BH3 mimetic drugs. We will also include in our studies candidate small molecules that emerge from the other Projects. Promising candidates will advance to clinical trials in collaboration with Clinical Core 3. For the first time, we propose to accelerate novel clinical trials in AML by using dynamic BH3 profiling to prioritize combinations that drive high apoptotic signaling in patient myeloblasts. In prior work, we have found that BH3 profiling can predict response to induction regimens in AML. We have installed BH3 profiling in a clinical laboratory where we can now test over a hundred AML samples per year. Building on our prior work, and working with Biostatistics Core 2, we will construct predictive biomarkers based on BH3 profiling for response to standard 7+3 induction, as well as to the newer venetoclax plus azacytidine. We will test inclusion into our predictive tool information like ELN criteria, age, and pathology. The expected output is a set of predictive tools that will offer likelihood of CR/CRi for individual patients for both induction regimens. It is hoped that this tool will help guide patients to the induction therapy that is best for them. While we exploit the concept of apoptotic priming to predict clinical response and identify active regimens in AML, we know little about the molecular determinants of the apoptotic priming phenotype. We will utilize genomic, transcriptomic, and proteomic tools to investigate the differences between myeloblasts in different states of apoptotic priming. While this work will focus on AML, it is expected that it will reveal principles of molecule determination of priming that will be applicable to other cell types.